A new study described the progression of liver disease in Wilson's disease (WD) by using a mouse model to examine the histological impact of copper overload.
Published in the Journal of Clinical Pathology, the study examined the stages of liver injury caused by copper accumulation, highlighting the role of inflammation, fibrosis, and atypia—and outlined potential benefits of chelation therapy.
WD is a rare genetic disorder caused by mutations in the ATP7B gene, disrupting copper transport and leading to toxic accumulation in the liver, brain, and other tissues. While WD is phenotypically diverse, liver involvement—ranging from asymptomatic changes to cirrhosis or acute liver failure—is common. However, early liver disease progression in WD remains poorly understood due to limited access to pre-symptomatic human samples, the authors noted.
This gap in knowledge prompted researchers to turn to animal models. Among them, the Atp7b−/− knockout mouse—a genetically engineered model—has emerged as a robust tool for studying WD-related liver pathology.
The study examined 138 Atp7b−/− mice across five age groups: 6, 20, 39, and 50 weeks, with and without copper chelation therapy. These groups were compared with 101 wild-type (WT) mice. The researchers performed comprehensive histological analyses to track liver injury progression.
Copper deposits in hepatocytes were detected as early as 6 weeks in Atp7b−/− mice but did not significantly increase over time. WT mice showed no copper deposition. Inflammation appeared by 6 weeks and progressively worsened, correlating with fibrosis, which became evident by 20 weeks. By 50 weeks, untreated Atp7b−/− mice displayed precirrhotic changes, while treated mice showed significantly reduced inflammation and fibrosis scores.
Significant cellular atypia, including nuclear enlargement and hepatocyte dysmorphia, emerged at 20 weeks and peaked by 39 weeks. Chelation therapy mitigated these changes but did not eliminate them. Nodular areas of regenerating liver tissue appeared in Atp7b−/− mice at 39 weeks. These nodules lacked copper deposits and were free of inflammation or fibrosis.
Unlike in human WD livers, steatosis was negligible, and no dysplastic or malignant changes were observed, aligning with the low malignancy risk typically seen in WD patients.
The study highlighted the efficacy of D-penicillamine, a copper-chelating agent, in reducing inflammation and fibrosis. However, the treatment did not reverse established nodular changes, underscoring the importance of early intervention.
Despite its strengths, the model has limitations. Unlike human WD, the mice do not exhibit neurological symptoms due to compensatory mechanisms in their brains, the authors wrote. Additionally, the absence of significant steatosis and malignancy in the mice highlights differences in disease manifestation.
Moving forward, researchers aim to extend the study duration to observe whether full cirrhosis or malignancy develops and to test novel therapeutic agents.
